1. Field of the Invention
The present invention relates to a method and compound for prevention and/or treatment of respiratory viral infection. More specifically, the present invention relates to blocking Respiratory Syncytial Virus binding to ICAM-1 via agents that interfere with binding or block the expression of ICAM-1.
2. Description of Related Art
Respiratory viruses such as respiratory syncytial virus (RSV), the parainfluenza viruses (PIV), and the influenza viruses cause severe lower respiratory tract diseases in infants and children throughout the world. It is also an important cause of disease in adults and is responsible for a significant amount of excess morbidity and mortality in the elderly. It also can be devastating in immunosuppressed populations (Murray et al., 1997; Pullen et al. 1982; Hall et al. 1984).
Experimental live attenuated vaccines for each of these viruses are being developed for intranasal administration in the first weeks or months of life, but none are currently FDA approved. A variety of RSV, PIV-3, and influenza virus vaccine strains have been developed by classical biological methods, evaluated extensively in preclinical and clinical studies, and shown to be attenuated and genetically stable. However, a major remaining obstacle to successful immunization of infants against respiratory virus associated disease may be the relatively poor immune response of very young infants to primary virus infection. (Crowe J E Jr Vaccine 1998 August-September; 16(14-15):1423-32 Immune responses of infants to infection with respiratory viruses and live attenuated respiratory virus candidate vaccines.)
Moreover, even if one or more vaccines are approved, they may not be suitable for some populations vulnerable to RSV (e.g. very young infants and the immunosuppressed). Ribavirin and immunoglobulin preparations with high titers of RSV-specific neutralizing antibodies are currently approved for use to treat and prevent RSV infection. However, neither of these methods are cost-effective or simple to administer. New agents are needed to reduce the impact of RSV. (Wyde P R Antiviral Res 1998 August; 39(2):63-79 Respiratory syncytial virus (RSV) disease and prospects for its control.
Data obtained from the National Respiratory and Enteric Virus Surveillance System demonstrates the seasonal pattern of RSV infection, with peak rates of 30-40% occurring at the beginning of each year (Murray et al., 1997; Pullen et al. 1982; Hall et al., 1984). RSV infection is commonly associated with interstitial lung diseases, such as bronchiolitis and asthma. It is a major risk factor for a number of other disease conditions, such as immunodeficiency, cardiac arrhythmia, congenital heart disease, and unusual atrial tachycardia (Sly, et al., 1989; Robinson et al. 1997; Armstrong et al. 1993; Fixler, 1996; Lemen, 1995; Persson, 1997; Shelhamer et al. 1995).
Although the severity of the disease decreases with repeated infection, previous RSV infection renders no or limited immunity to subsequent RSV infection (Hal, 1991).
Despite the above serious implications of RSV infection, the progress in the knowledge of the viral genes and gene products (Collins, 1991; Collins et al., 1996; Barik, 1992), an effective vaccine, or treatment against RSV, is yet to be developed.
Additionally, previous attempts to develop a vaccine using formalin inactivated RSV not only failed but exacerbated the disease when subsequent RSV infection occurred (Chanock, et al. 1992; Hall, 1994). An effective vaccine or treatment for RSV would be highly desirable.
Additionally, human nasal, airway, and lung epithelial cells constitute a major target for respiratory infections. Viral infection alters the expression of genes encoding a number of cytokines, chemokines and inflammatory mediators (Sabauste, et al. 1995; Choi, et al. 1992; Becker et al. 1993.
The secretion of cytokines by airway epithelial cells can either initiate local inflammatory responses or amplify an inflammatory event that was previously initiated by activated macrophages, eosinophils, mast cells or lymphocytes (Shelhamer et al., 1995; Holtzman, et al. 1991; Churchill, et al. 1989; Marini, et al. 1992; Churchill, et al. 1992; Kwon, et al. 1994; Sousa, et al. 1994; Cromwell, et al. 1992; Jin, et al. 1997). The epithelial cell-mediated inflammation by involve a number of cytokines and chemokines including IL-1β, IL-6, IL-8, IL-11, IFN-γ, TNF-α, GM-CSF, GRO-α, PLA-2, C3, inducible nitric oxide synthase (iNOS), MCP-1, endothelin-1 (ET-1), mucin, elastase-specific inhibitors, and secretory leukocyte proteinase inhibitor.
The rhinovirus infection of a transformed HBE cell line, BEAS-2B, caused the release of the granulocyte macrophage colony stimulating factor (GM-CSF), IL-6, and IL-8 (Sabauste et al. 1995). The influenza virus infection of primary cultures of human bronchial epithelial (HBE) cells induced the expression of IL-8 (Choi, et al. 1992). Also, in response to RSV infection, nasal epithelial cells and BEAS-2B cells generated IL-8 (Becker et al., 1993; Merolla et al., 1995; Noah, et al., 1993; Garofalo et al. 1996).
It is known that, when infected bronchial epithelial cells secrete several pro-inflammatory cytokines, as set forth above. Some of these cytokines (IL-1β, TNF-2) up-regulate ICAM-1 expression on these cells (Persson et al., 1997; Becker et al., 1993; Noah et al., 1993; Sabauste et al., 1995). ICAM-1, a member of the immunoglobulin gene super family, is a cell surface receptor for the lymphocyte function-associated antigen (LFA-1) adhesion molecule (Makgoba et al., 1998). ICAM-1 mediates the integration of leukocytes into inflammatory sites and facilitates interaction between lymphocytes and target cells. ICAM-1 is also the major cell surface receptor for many of the rhinoviruses (Greve et al., 1989; Staunton et al., 1989; Tomassini et al., 1989).
RSV, though phylogenetically different from rhinovirus, induces a similar profile of cytokines in epithelial cells and also NF-κB, which regulates expression of ICAM-1 that plays a role in neutrophil and eosinophil adhesion to epithelial cells (Arnold et al., 1995; Chini et al., 1998; Stark et al., 1996). Also an elevated expression of ICAM-1 in nasal epithelial cells of asthmatics has been reported (Vignola et al., 1993).